Clozapine is the most effective
antipsychotic drug for
schizophrenia, yet it can cause life-threatening
adverse drug reactions, including
myocarditis. The aim of this study was to determine whether
schizophrenia patients with
clozapine-induced
myocarditis have a
genetic predisposition compared with
clozapine-tolerant controls. We measured different types of genetic variation, including genome-wide single-nucleotide polymorphisms (SNPs), coding variants that alter
protein expression, and variable forms of human leucocyte
antigen (HLA) genes, alongside traditional clinical risk factors in 42 cases and 67 controls. We calculated a
polygenic risk score (PRS) based on variation at 96 different genetic sites, to estimate the genetic liability to
clozapine-induced
myocarditis. Our genome-wide association analysis identified four SNPs suggestive of increased
myocarditis risk (P < 1 × 10-6), with odds ratios ranging 5.5-13.7. The SNP with the lowest P value was rs74675399 (chr19p13.3, P = 1.21 × 10-7; OR = 6.36), located in the GNA15 gene, previously associated with
heart failure. The
HLA-C*07:01 allele was identified as potentially predisposing to
clozapine-induced
myocarditis (OR = 2.89, 95% CI: 1.11-7.53), consistent with a previous report of association of the same allele with
clozapine-induced
agranulocytosis. Another seven HLA alleles, including
HLA-B*07:02 (OR = 0.25, 95% CI: 0.05-1.2) were found to be putatively protective. Long-read
DNA sequencing provided increased resolution of HLA typing and validated the HLA associations. The PRS explained 66% of liability (P value = 9.7 × 10-5). Combining clinical and genetic factors together increased the proportion of variability accounted for (r2 0.73, P = 9.8 × 10-9). However, due to the limited sample size, individual genetic associations were not statistically significant after correction for multiple testing. We report novel candidate genetic associations with
clozapine-induced
myocarditis, which may have potential clinical utility, but larger cohorts are required for replication.